Interleukin-31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge (original) (raw)
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New mechanism underlying IL-31-induced atopic dermatitis
The Journal of allergy and clinical immunology, 2018
T2 cell-released IL-31 is a critical mediator in patients with atopic dermatitis (AD), a prevalent and debilitating chronic skin disorder. Brain-derived natriuretic peptide (BNP) has been described as a central itch mediator. The importance of BNP in peripheral (skin-derived) itch and its functional link to IL-31 within the neuroimmune axis of the skin is unknown. We sought to investigate the function of BNP in the peripheral sensory system and skin in IL-31-induced itch and neuroepidermal communication in patients with AD. Caimaging, immunohistochemistry, quantitative real-time PCR, RNA sequencing, knockdown, cytokine/phosphokinase arrays, enzyme immune assay, and pharmacologic inhibition were performed to examine the cellular basis of the IL-31-stimulated, BNP-related itch signaling in dorsal root ganglionic neurons (DRGs) and skin cells, transgenic AD-like mouse models, and human skin of patients with AD and healthy subjects. In human DRGs we confirmed expression and co-occurrenc...
IL-31 Expression by Inflammatory Cells is Preferentially Elevated in Atopic Dermatitis
Acta Dermato Venereologica, 2012
Interleukin-31 (IL-31) is a recently discovered cytokine expressed in many human tissues, and predominantly by activated CD4 + T cells. IL-31 signals through a heterodimeric receptor consisting of IL-31 receptor alpha (IL-31RA) and oncostatin M receptor beta (OSMR). Earlier studies have shown involvement of IL-31 and its receptor components IL-31RA and OSMR in atopic dermatitis, pruritus and Th2-weighted inflammation at the mRNA level. The aim of this study was to investigate IL-31 protein expression in skin of such conditions. Immunohistochemical staining for IL-31, IL-31RA and OSMR was performed in formalin-fixed paraffin-embedded biopsy specimens. IL-31 expression was increased in the inflammatory infiltrates from skin biopsies taken from subjects with atopic dermatitis, compared with controls (p ≤ 0.05).
2022
Background: Itching is one of the major and mandatory signs of atopic dermatitis (AD) in children. Interleukin 31 (IL-31) is strongly involved in the genesis of pruritus. In our study, 68 patients aged 0-18 years with proven AD were followed clinically. The role of IL-31 in pruritus as clinical manifestation of AD is known but its etiopathogenetic mechanism is not well known. Methods: Serum was collected from 31 patients with moderate and severe forms of AD to determine IL-31 and its correlation with activity and severity of the disease. We also studied 30 healthy patients to compare the results of determinations. The IL-31 value was determined using the sandwich enzyme-linked-immunosorbent serologic assay (two antibodies assay). The IL-31 values were expressed as picograms per milliliter (pg/mL) and compared with activity and severity of the disease. Results: The IL-31 value was much higher in patients with AD compared to the control group. The mean value of findings was 1600 pg/mL compared to the control group with an average of 220 pg/mL. The IL-31 values were positively correlated with the severity and activity of the disease. Conclusions: The results of our pediatric study established the involvement of IL-31 in the pathophysiology of AD. IL-31 could be a marker of AD track.
Blockage of the IL-31 Pathway as a Potential Target Therapy for Atopic Dermatitis
Pharmaceutics
Atopic dermatitis (AD), a pruritic, inflammatory chronic disease with multifactorial pathogenesis, has been a therapeutic challenge. Novel target treatments aim to reduce not only the immunologic dysfunction and microbiome dysbiosis but also the recovery of the damaged skin barrier. The current review focuses on the interleukin 31 (IL-31) pathway and AD and offers an overview of the current clinical studies with monoclonal antibodies blocking this cascade. Pruritus, the key symptom of AD, has substantial participation of the IL-31 complex and activation of relevant signaling pathways. Epidermal keratinocytes, inflammatory cells, and cutaneous peripheral nerves express the interleukin-31 receptor α-chain (IL-31RA), upregulated by Staphylococcus aureus toxins or Th2 cytokines involved in AD. Nemolizumab is a humanized monoclonal antibody that antagonizes IL-31RA, inhibiting the IL-31 cascade and therefore contributing to reducing the pruritus and inflammation and recovering the damage...
Clinical, Cosmetic and Investigational Dermatology
Background: Pruritus is the most common symptom in patients with skin disease. Psoriasis and atopic dermatitis are clinically distinct inflammatory diseases. Interleukins are cytokines which play key roles in inflammatory signaling pathways. Materials and Methods: Cross-sectional study was conducted among patients with psoriasis and atopic dermatitis: 59 psoriatic patients, 56 AD patients, and 49 matched healthy controls. Interleukins 4, 13, 31, 33 serum levels were assayed by ELISA and results were compared using SPSS. Itch severity and disease severity were measured and correlation with interleukin levels was determined using SPSS. Results: The serum levels of IL-4,-13,-31,-33 were elevated in atopic dermatitis patients compared to controls. Itch and disease severity were not correlated with elevated serum levels of these interleukins. In psoriasis, the levels of IL-4 and-31 were elevated compared to controls, whereas the levels of IL-13 and-33 were lower than controls. The levels of measured interleukins in psoriasis did not correlate with itch and disease severity. Conclusion: IL-31 is the key mediator for pruritus in both AD and Ps patients. IL-4/31 axis and IL-33/13 axis play distinct roles in the pathogenesis of Atopic dermatitis and Psoriasis. Interleukin serum levels were not correlated with itch and disease severity in both conditions.
British Journal of Dermatology, 2012
Background Itch is the cardinal symptom of atopic dermatitis (AD). b-Endorphin, a neuropeptide, is increased in both AD skin and sera. Interleukin (IL)-31, an itch-relevant cytokine, activates IL-31 receptors in keratinocytes. However, how IL-31 and b-endorphin interact in AD skin remains elusive. Objectives To investigate the mechanistic interaction of IL-31 and b-endorphin in AD. Methods This was a prospective cross-sectional study. We recruited adult patients with AD and controls according to Hanifin’s AD criteria. Serum levels of IL-31 and b-endorphin were measured by enzyme-linked immunosorbent assay. Expressions of IL-31 receptor A (IL-31RA) and b-endorphin in the skin were assessed by immunohistochemistry. Their expression in the skin and blood was compared and correlated in patients with AD and in controls. We also treated primary keratinocytes with IL-31 and measured calcium influx, b-endorphin production and signalling pathways to define their mechanistic interactions. Results b-Endorphin was increased in the supernatant from IL-31-treated keratinocytes. IL-31 receptor activation resulted in calcium influx and STAT3 activation; pretreatment with STAT3 inhibitor stopped the increase of b-endorphin. Notably, either replacement of extracellular calcium or treatment with 2-aminoethoxydiphenyl borate, an inhibitor for the store-operated channel, blocked STAT3 activation. We found higher levels of blood b-endorphin and IL-31, which were significantly correlated, in patients with AD. Moreover, IL-31RA and b-endorphin were increased and colocalized both in AD human skin and TPA-painted mouse skin. Conclusions IL-31 receptor activation in keratinocytes induces calcium influx and STAT3-dependent production of b-endorphin. These results might contribute to an understanding of the regulatory mechanisms underlying peripheral itch.
Journal of Allergy and Clinical Immunology, 2006
Background: IL-31 is produced by activated T lymphocytes, preferentially by T H 2 cells. Transgenic mice overexpressing IL-31 have a phenotype resembling allergic dermatitis in human subjects. Objective: We sought to evaluate the potential importance of IL-31 in the pathogenesis of human T cell-mediated skin diseases. Methods: We analyzed total RNA taken from 149 skin biopsy specimens from patients with atopic dermatitis (AD), allergic contact dermatitis (ACD), or psoriasis in comparison with specimens taken from patients with healthy skin (n 5 13) by using quantitative real-time PCR for the expression of T H 1/T H 2 cytokines. Results: We found statistically increased mRNA levels of IL-31 in biopsy specimens taken from patients with AD, irrespective of the severity of the disease and serum IgE levels. Moreover, IL-31 mRNA levels were strongly increased in many biopsy specimens taken from patients with ACD. However, no increased transcription of IL-31 could be detected in biopsy specimens taken from psoriatic plaques. A comparison of mRNA levels of IL-31 with T H 1 or T H 2 cytokines demonstrates a correlation of the expression of IL-31 with IL-4 and IL-13 but not with IFN-g. No significant increase of IL-31 receptor mRNA could be detected in any disease, whereas the second receptor subunit of IL-31, the oncostatin M receptor, seems to be enhanced transcribed in patients with psoriasis.
Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice
Nature Immunology, 2005
T cell-derived cytokines are important in the development of an effective immune response, but when dysregulated they can promote disease. Here we identify a four-helix bundle cytokine we have called interleukin 31 (IL-31), which is preferentially produced by T helper type 2 cells. IL-31 signals through a receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL-31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes, whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice overexpressing IL-31 developed severe pruritis, alopecia and skin lesions. Furthermore, IL-31 receptor expression was increased in diseased tissues derived from an animal model of airway hypersensitivity. These data indicate that IL-31 may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.
Increased levels of serum IL-31 in chronic spontaneous urticaria
Experimental Dermatology, 2010
IL-31represents a novel cytokine involved in pruritic skin diseases including atopic dermatitis (AD). We, therefore, aimed at investigating IL-31 levels in chronic spontaneous urticaria (CU). We included 46 patients with CU, 26 non-atopic skin healthy subjects as negative and 28 patients with AD as positive controls. IL-31 serum levels were analysed using commercial ELISA kit. IL-31 serum levels were higher in patients with CU compared to healthy controls (P < 0.001), but lower compared to patients with AD (P < 0.001). There was no difference in IL-31 serum levels in autologous serum skin test positive or negative CU patients and patients with infectious trigger factors including helicobacter pylori infection. IL-31 serum levels may play a role in the pathophysiology of CU. This is supported by the finding that not all patients with CU respond to antihistamine treatment but to the treatment with immunosuppressive drugs.